Unraveling the therapeutic potential of the Hedgehog pathway in cancer

Amakye, Dereck D.; Jagani, Zainab; Dorsch, Marion

doi:10.1038/nm.3389

Cited by 496 publications

(503 citation statements)

References 121 publications

Supporting

Mentioning

488

Contrasting

Unclassified

Order By: Relevance

“…However, the state of the art regarding the role of the stroma in promoting pancreatic tumor progression and the role of the Hh signaling pathway as a master regulator of this dangerous desmoplastic reaction have been shaken very recently with two important papers describing that stromal abolishment (either through depletion of tumor fibroblasts or by deleting Hh in the pancreas) leads to increased survival in K-Ras driven mice models of pancreatic cancer [53,54] . These data contradicts previous similar in vivo works in which targeting the stromal compartment resulted in an improvement on chemotherapy delivery and increased survival [3][4][5] and try to explain the big disappointments that the medical community has faced upon trying Hh inhibitors in clinical trials [55] . However, these studies should be taken with caution because the genetic strategies used lead to almost a complete disruption of the tissue surrounding the tumor mass.…”

Section: Research Highlightcontrasting

confidence: 63%

Galectin-1 as a therapeutic target in pancreatic cancer: the tumor stroma in the spotlight

Martínez-Bosch

Navarro

2014

Can Cell Microenviron

View full text Add to dashboard Cite

Treating pancreatic cancer is one of the great challenges in cancer research and identification of new strategies is a must, considering the poor efficiency of standard chemotherapy and current patients' dismal prognosis. We have recently identified Galectin-1 as a master regulator driving pancreatic cancer progression in the Ela-myc model. Interestingly, Galectin-1 depletion in these tumors not only results in decreased tumor cell proliferation but also in a profound remodeling of the desmoplastic reaction, impairing angiogenesis, stroma activation and boosting the animal immune response. Intriguingly, our experimental data indicate that Galectin-1 regulates the Hedgehog signaling pathway, which may well be responsible for some of the effects driven by the lectin in pancreatic cancer. We herein discuss how Galectin-1 may remodel the tumor microenvironment in this pathology and highlight its potential as a therapeutic target.

show abstract

Section: Research Highlightcontrasting

confidence: 63%

Galectin-1 as a therapeutic target in pancreatic cancer: the tumor stroma in the spotlight

Martínez-Bosch

Navarro

2014

Can Cell Microenviron

View full text Add to dashboard Cite

show abstract

“…S6A). GLI transcription factors are important downstream transcription factors of Hedgehog signaling, which plays key roles in embryonic development and maintenance of adult tissues (34) and is known to be altered in multiple cancers (35). To investigate whether Hedgehog signaling activated in lung adenocarcinoma, we first analyzed mRNA expression of genes involved in Hedgehog signaling in tumors in vivo.…”

Section: Resultsmentioning

confidence: 99%

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Narayana

Xia

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Lung adenocarcinoma, a major form of non-small cell lung cancer, is the leading cause of cancer deaths. The Cancer Genome Atlas analysis of lung adenocarcinoma has identified a large number of previously unknown copy number alterations and mutations, requiring experimental validation before use in therapeutics. Here, we describe an shRNA-mediated high-throughput approach to test a set of genes for their ability to function as tumor suppressors in the background of mutant KRas and WT Tp53. We identified several candidate genes from tumors originated from lentiviral delivery of shRNAs along with Cre recombinase into lungs of Loxp-stop-Loxp-KRas mice. Ephrin receptorA2 (EphA2) is among the top candidate genes and was reconfirmed by two distinct shRNAs. By generating knockdown, inducible knockdown and knockout cell lines for loss of EphA2, we showed that negating its expression activates a transcriptional program for cell proliferation. Loss of EPHA2 releases feedback inhibition of KRAS, resulting in activation of ERK1/2 MAP kinase signaling, leading to enhanced cell proliferation. Intriguingly, loss of EPHA2 induces activation of GLI1 transcription factor and hedgehog signaling that further contributes to cell proliferation. Small molecules targeting MEK1/2 and Smoothened hamper proliferation in EphA2-deficient cells. Additionally, in EphA2 WT cells, activation of EPHA2 by its ligand, EFNA1, affects KRAS–RAF interaction, leading to inhibition of the RAS-RAF-MEK-ERK pathway and cell proliferation. Together, our studies have identified that (i) EphA2 acts as a KRas cooperative tumor suppressor by in vivo screen and (ii) reactivation of the EphA2 signal may serve as a potential therapeutic for KRas-induced human lung cancers.

show abstract

“…For example, Hh signaling appears to modulate the response to EGFR signaling in head and neck squamous cell carcinoma (25); dual inhibition of both the Hh and EGFR pathways is therefore an intriguing strategy. In addition, evidence of cross-talk between the Hh and PI3K-mTOR pathways suggests that combined inhibition may be of value; a clinical trial evaluating the Hh inhibitor sonidegib plus the PI3K inhibitor buparlisib has been initiated (26,27).…”

Section: Discussionmentioning

confidence: 99%

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Goldman¹,

Eckhardt

Borad

et al. 2015

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: This first-in-human study assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of single and multiple doses of TAK-441, an investigational inhibitor of the Hedgehog signaling pathway.Experimental Design: Patients with advanced, solid tumors received daily oral TAK-441 (50-1,600 mg/day); daily dose was doubled in each subsequent cohort until the maximum tolerated/ feasible dose (MTD/MFD) was reached. Blood was collected to evaluate TAK-441 plasma concentrations. Skin biopsies were obtained to evaluate suppression of the Hedgehog-regulated gene Gli1.Results: Thirty-four patients were enrolled (median age 59). The most common diagnoses were colorectal cancer (26%), basal cell carcinoma (BCC, 21%), and pancreatic cancer (9%). The MFD of 1,600 mg/day (based on tablet size and strength) was considered the MTD. Dose-limiting toxicities included muscle spasms and fatigue. Grade !3 treatment-emergent adverse events, regardless of causality, occurred in 15 patients (44%), of which hyponatremia (n ¼ 4) and fatigue (n ¼ 3) were most common. Oral absorption was fairly rapid; median T max was 2.0 to 4.0 hours after a single dose. Mean elimination half-life was 13.5 to 22.6 hours. Systemic exposure of TAK-441 based on the area under the plasma concentrationtime curve was linear across the dose range. Gli1 expression in skin biopsies was strongly inhibited at all dose levels. Best response was partial response (1 patient with BCC) and stable disease (7 patients with various solid tumors).Conclusions: TAK-441 was generally well tolerated up to MFD of 1,600 mg/day, with preliminary antitumor activity. Further study of TAK-441 may be appropriate in populations selected for tumors with ligand-dependent or independent Hedgehog signaling.

show abstract

Unraveling the therapeutic potential of the Hedgehog pathway in cancer

Cited by 496 publications

References 121 publications

Galectin-1 as a therapeutic target in pancreatic cancer: the tumor stroma in the spotlight

Galectin-1 as a therapeutic target in pancreatic cancer: the tumor stroma in the spotlight

Screening for tumor suppressors: Loss of ephrin receptor A2 cooperates with oncogenic KRas in promoting lung adenocarcinoma

Phase I Dose-Escalation Trial of the Oral Investigational Hedgehog Signaling Pathway Inhibitor TAK-441 in Patients with Advanced Solid Tumors

Contact Info

Product

Resources

About